The Wonder Drug Myth

Even the pharmaceutical industry's best products are imperfect, working in only half—or fewer—patients. It's time for better targeting.

In the past 50 years, modern pharmacology has created dozens of treatments that improve and save lives. Cardiovascular drugs like beta- blockers have drastically reduced deaths from heart attacks and heart disease. For every million people who take a statin drug for high cholesterol, there are 50,000 fewer angioplasties, surgeries, heart attacks, strokes, and cardiovascular deaths, studies have shown. And in the past 15 years, drugs have transformed AIDS from a death sentence into a managed disease. These are just some of the triumphs of pharmacology, and each case is a bona fide miracle, a life transformed.

But not every drug can deliver a fairy-tale ending. Many of the stories we expect from drugs are partly fictions, hiding in a gauze of ambiguous results, placebo effects, and messy side effects. Though it’s widely known that the pharmaceutical industry tests hundreds of substances to get the handful that work, most people assume that those that are approved by the Food and Drug Administration (FDA) are actually effective. But the numbers say otherwise.

Even the best drugs have imperfect chances of working for any one person. Asthma drugs work in about 60 percent of patients. Migraine drugs are effective in only about half of cases. Drugs for Alzheimer’s disease work in about 30 percent of patients. And those are exceptional results compared to cancer drugs, which at best work about 25 percent of the time.

What’s more, despite advances, the pipeline of new drugs has slowed to a crawl, as one promising candidate after another has petered out in the last phases of development. "The low-hanging fruit has been picked," says Derek Lowe, PhD, a drug discovery chemist and industry pundit. William Haseltine, PhD, a former researcher at Harvard Medical School and the founder of Human Genome Sciences and eight other biotechnology companies, notes that fewer than 1 in 100 new ideas reaches clinical trials and fewer than 10 percent of these are approved for sale.

This high failure rate means that the few drugs that do get through the gauntlet of clinical trials and FDA approval become must-win propositions. A company must pull out all the stops to sell the drug, which means marketing.

The drug industry’s intense marketing to physicians has been well covered. But it’s worth noting here that some marketing is designed to push out perfectly worthwhile older treatments (whose patent protection has often expired and can therefore be sold as cheap generics) in order to advance newer treatments (which are under patent protection, and therefore are more expensive).

But are the new drugs really better? The FDA doesn’t require comparative clinical trials, only proof that the drug beats a placebo. So unless somebody were to compare drugs head to head, it’s almost impossible to say. That was the premise behind a landmark study by the name of ALLHAT (short for Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), begun in 1994. Various treatments for high blood pressure were compared side by side in order to see, once and for all, which treatment was really best.  At the time the study began, the use of diuretics and beta-blockers was in decline, while three newer treatments—calcium channel blockers, angiotensin-converting enzyme inhibitors (known as ACE inhibitors), and alpha-adrenergic blockers—were on the rise. But since these newer drugs had only been compared to placebo when working their way to FDA approval, there was no way to know which treatment was most effective.

The study, which recruited 42,000 individuals with elevated blood pressure, was one of the most ambitious ever carried out for the condition. The subjects were divided into four groups and given one of four treatments: a diuretic, an ACE inhibitor, a calcium channel blocker, or an alpha blocker. Within a few years, the alpha blocker arm of the trial was stopped: Patients were showing a 25 percent increased risk of heart disease. The other 30,000 patients continued their protocols for 5 years, and then the results were analyzed.

Published in 2002 and elaborated upon in 2006, the results were a disaster for the drug industry. Not only was the alpha blocker deemed too suspect to use, but the calcium antagonist and the ACE inhibitor both fell short of the cheap, common, and old-fashioned diuretic in lowering blood pressure and reducing the risk of heart disease. Patients on the newer, patented drugs had higher rates of stroke and heart failure.

The ALLHAT researchers could hardly contain their glee. “This should really cause us to stop and think about defining what ‘better’ means in terms of real outcomes and not sales pitches,” said Robert Califf, MD, a cardiologist at Duke Medicine and a member of the ALLHAT Data and Safety Monitoring Board, when the results became public.  “The real news here is, Who knows what other inexpensive generic drugs that are actually better are not being used because there’s no one out there selling them to doctors?”

But even for many drugs that have been around for decades, the data is disturbingly murky with respect to what they actually do for whom, and who should or should not be taking them.

There’s no doubt that aspirin is something of a magic bullet.  Acetylsalicylic acid, as aspirin is technically known, works by blocking prostaglandins—powerful chemicals in the body that cause swelling and inflammation. Since prostaglandins also cause blood to clot, small doses of aspirin have been found to reduce the risk of stroke and heart attack (millions of people take them every day for this purpose). Aspirin has also been found to slow the progress of some forms of dementia, and it could reduce the risk of Alzheimer’s disease. It even suppresses estrogen levels in women, reducing the risk of breast cancer.

It’s been said, though, that had Bayer compounded the first stable form of aspirin yesterday, rather than 110 years ago, it would never get FDA approval. The problem is twofold: For one, aspirin doesn’t really work like a magic “bullet” at all; it’s more like a shotgun, having scattered effects on many different systems within the body. This is contrary to the current industry preference for drugs that work like bullets, hitting single, precise targets. And second, aspirin has long been known to come with side effects. It can cause serious gastric bleeding in some people, and it can cause Reye’s syndrome, a potentially fatal neurological disease, in children. These side effects would be red flags to today’s drug developers.

Tylenol, though, would have it even worse. Derived from coal tar, acetaminophen, the active chemical in Tylenol, was first introduced into medical practice in the 1880s. It was used sporadically until the 1950s, when Tylenol was introduced and marketed as being safer than aspirin because it was suitable for children and was easier on the stomach. The pitch worked, and Tylenol became the best-selling health product in the United States, with higher sales than Crest toothpaste. Today, acetaminophen is the most widely used pain reliever in the world.

But acetaminophen can be a profoundly dangerous drug. For some people, it is pure poison. Acetaminophen is the most common cause of liver failure in the United States, where about 50 percent of cases are attributed to acetaminophen toxicity, according to a 2005 study. This risk has been well known for more than a decade and has generally been associated with failing to follow the directions, taking too much acetaminophen, or combining the pain reliever with alcohol.

More recently, though, another less celebrated red flag has also been raised about the drug. In May 2009, researchers from the University of North Carolina in Chapel Hill and the Jackson Laboratory in Bar Harbor, Maine, suggested that in some people who suffered liver failure after taking the drug, the cause may be genetic, not the size of the dose.

The researchers found that in as many as one-third of healthy individuals, even a normal dose of acetaminophen dangerously raised blood levels of alanine transferase, a liver enzyme, suggesting damage to the liver. The researchers found that a single-letter (or SNP) variation on a gene known as CD44 was significantly associated with liver injury.

“The reality is that there is no safe drug,” said Paul Watkins, a coauthor of the study. “Good drugs are bad for some people. Because different people respond differently to drugs, where you draw the line is not exactly black and white.”

For most drugs – new or old – efforts are rarely made to determine who should really be taking them. After all, if a drug that's effective in 50 percent of people is taken only by those for whom it works, that would mean half as many people buying it. But when follow-up research is conducted on how drugs work in different people, it can be remarkably revealing and beneficial.

It's high time for an era of research that takes the extra step so that drugs can be better matched to individuals. Identifying drugs that are safe and effective for each person doesn’t mean having to wait for billion-dollar wonder drugs that work on everyone.